Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation.
Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation.
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长 3UTR 通过促进免疫刺激性双链 RNA 的形成而使神经元容易发生炎症。
DOI：
10.1126/sciimmunol.adg2979
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发表时间：
2023
影响因子：
24.8
通讯作者：
Wichterle,
中科院分区：
文献类型：
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作者：
Dorrity,TylerJ;Shin,Heegwon;Wiegand,KenenniA;Aruda,Justin;Closser,Michael;Jung,Emily;Gertie,JakeA;Leone,Amanda;Polfer,Rachel;Culbertson,Bruce;Yu,Lisa;Wu,Christine;Ito,Takamasa;Huang,Yuefeng;Steckelberg,Anna-Lena;Wichterle,
RNA稳态的丧失是许多神经退行性和神经炎性疾病的基础。然而，触发神经炎症的分子机制知之甚少。病毒双链RNA（dsRNA）在被存在于所有细胞类型中的宿主模式识别受体（PRR）感知时触发先天免疫应答。在这里，我们报告说，人类神经元固有地携带异常高水平的免疫刺激性dsRNA，并确定长3′ UTR作为产生神经元dsRNA结构。我们发现神经元富集的ELAVL基因家族（ELAVL 2、ELAVL 3和ELAVL 4）可以增加（i）3′UTR长度，（ii）dsRNA负载，和（iii）dsRNA敏感PRRs如MDA 5、PKR和TLR 3的激活。在野生型神经元中，神经元dsRNA通过PRR发出信号以诱导抗病毒I型干扰素的紧张性产生。WT神经元中ELAVL 2缺失导致3′UTR长度整体缩短，免疫刺激性dsRNA水平降低，并使WT神经元对单纯疱疹病毒和寨卡病毒感染易感。缺乏ADAR 1（一种在神经炎性疾病Aicardi-Goutières综合征中突变的dsRNA编辑酶）的神经元表现出不可耐受的高水平dsRNA，引发了PRR介导的毒性炎症和神经元死亡。在ADAR 1基因敲除的神经元中缺失ELAVL 2通过降低免疫刺激性dsRNA水平导致神经元存活延长。总之，神经元是专门的细胞，其中PRR不断地感测“自身”dsRNA以抢先诱导保护性抗病毒免疫，但维持RNA稳态对于预防病理性神经炎症至关重要。
Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3′UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2,ELAVL3, andELAVL4) can increase (i) 3′UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. DepletingELAVL2in WT neurons led to global shortening of 3′UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. DepletingELAVL2in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense “self” dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.